CN1129219A - Pharmaceutical compounds - Google Patents

Pharmaceutical compounds Download PDF

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CN1129219A
CN1129219A CN95117133A CN95117133A CN1129219A CN 1129219 A CN1129219 A CN 1129219A CN 95117133 A CN95117133 A CN 95117133A CN 95117133 A CN95117133 A CN 95117133A CN 1129219 A CN1129219 A CN 1129219A
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compound
alkyl
hydrogen
indoles
tetrahydrochysene
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CN1045602C (en
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J·吉尔摩
P·T·加拉赫
M·V·迈尔斯
W·M·奥顿
C·W·史密夫
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Lilly Industries Ltd
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Lilly Industries Ltd
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Priority claimed from GB9418326A external-priority patent/GB9418326D0/en
Priority claimed from GBGB9511166.2A external-priority patent/GB9511166D0/en
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Abstract

A pharmaceutical compound and salts and solvates of the formula (I), where each group's definition is appeared in specification.

Description

Medicinal compound
The present invention relates to medicinal compound, their preparation and application.
Compound of the present invention is following formula: compound and salt and solvate
Figure A9511713300061
R wherein 1And R 7Each is halogen, trifluoromethyl, C naturally 1-6Alkyl, C 1-6Alkoxyl group, the heteroaryl of selecting phenyl, the naphthyl of selecting replacement that replaces or selecting to replace; R 2And R 3Each is hydrogen or C naturally 1-6Alkyl; R 4And R 5Each is hydrogen, halogen, trifluoromethyl, C naturally 1-6Alkyl C 1-6Alkoxyl group, the heteroaryl of selecting phenyl, the naphthyl of selecting replacement that replaces or selecting to replace; R 6Be hydrogen, C 1-6The heteroaryl that alkyl, the phenyl of selecting replacement, the naphthyl of selecting replacement, selection replace, phenyl-C that selection replaces 1-6Alkyl or-CO 2R 8, R wherein 8It is ester group; M and p each naturally 0,1,2,3 or 4, n is 1,2,3 or 4, Z is
Figure A9511713300071
,-O-,-S-or R wherein 9And R 10Each is hydrogen, C naturally 1-6Phenyl-C that alkyl or selection replace 1-6Alkyl; X is oxygen or sulphur; And Y is
Figure A9511713300073
Or
Figure A9511713300074
R wherein 11And R 12Each is hydrogen, C naturally 1-6The phenyl that alkyl, trifluoromethyl, selection replace, the heteroaryl of selecting the naphthyl that replaces or selecting to replace.
The compounds of this invention can be used for treating the disease of central nervous system, and they have activity in the test that serotoninergic adjustment function can be described.
Above-mentioned formula (I) compound comprises two groups of compounds:
Figure A9511713300075
Preferred formula (II) wherein.
Preferred one group of compound is a following formula: compound:
Figure A9511713300082
In formula (I) above, C 1-6Alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, amyl group and hexyl, preferable methyl or ethyl.C 1-6Alkoxyl group is that a kind of above-mentioned group is connected on the ring by Sauerstoffatom, and the preferred chlorine of halogen atom, bromine or fluorine, particularly chlorine or fluorine.
The phenyl that replaces is to have one or morely, and as the phenyl that one to three substituting group replaces, substituting group is selected from for example C 1-4Alkyl, particularly methyl C 1-4Alkoxyl group, particularly methoxyl group and oxyethyl group, hydroxyl, nitro, cyano group, halogen, particularly chlorine or fluorine; Trihalomethyl group, particularly trifluoromethyl; Carboxyl and C 1-4Carbalkoxy.Phenyl-the C that replaces 1-6Alkyl is to have one or more these type of groups, the preferred benzyl that replaces on phenyl ring.The naphthyl or the heteroaryl that replace also can have one or more above-mentioned substituting groups.Select the phenyl-C of replacement 1-6The preferred benzyl of alkyl.
Ester group can be aliphatic series or aromatics, and most preferred ester is by C 1-4Alkanol deutero-alkyl ester, particularly methyl ester and ethyl ester.
Heteroaryl can have and one or morely is selected from for example heteroatoms of oxygen, nitrogen and sulphur, and preferably contains 5-10 carbon atom.Preferred heteroaryl is the following formula group:
Figure A9511713300091
Wherein Q be-O-,-S-or-NR-, and R is hydrogen or C 1-6Alkyl.In addition, heteroaryl can contain a benzene condensed ring, for example: Also have, heteroaryl comprises the following formula group:
Figure A9511713300101
With
Figure A9511713300102
Preferred compound is the compound with one or more following characteristics:
(ⅰ) X is an oxygen;
(ⅱ) Z is , and R 9Be hydrogen or C 1-6Alkyl;
(ⅲ) R 9Be hydrogen;
(ⅳ) R 1Be halogen, C 1-6Alkyl or C 1-6Alkoxyl group;
(ⅴ) m is 0,1 or 2;
(ⅵ) p is 0,1 or 2;
(ⅶ) R 2And R 3Be hydrogen;
(ⅷ) R 4Be hydrogen;
(ⅸ) R 5Be hydrogen, trifluoromethyl or C 1-6Alkyl;
(ⅹ) R 5Be hydrogen;
(ⅹ ⅰ) R 6Be hydrogen;
(ⅹ ⅱ) R 7Be halogen, trifluoromethyl C 1-6Alkyl or C 1-6Alkoxyl group;
(ⅹ ⅲ) R 11And R 12Be hydrogen.
As more than one R 1Or more than one R 7During group, they can be identical or different certainly.In addition, when n is 2,3 or 4, be connected in the R on each carbon atom 2And R 3Value also not necessarily identical.
Preferred one group of compound is following formula: compound and its salt;
Figure A9511713300111
R wherein 9Be hydrogen or C 1-6Alkyl, R 1 ', R 1 ", R 7 'And R 7 "Each is hydrogen, halogen, C naturally 1-6Alkyl or C 1-6Alkoxyl group, R 5Be that hydrogen or trifluoromethyl and Y are:
Figure A9511713300112
Or
Figure A9511713300113
Obviously, The compounds of this invention can contain one or more unsymmetrical carbons, produces multiple isomer thus.Above-claimed cpd prepares with the racemic mixture form usually, and can use with this form easily, but can isolate single isomer with routine techniques if desired.These racemic mixtures and single optical isomer form are integral parts of the present invention.The preferred form of using enantiomer-pure.
Certainly, can prepare the salt of The compounds of this invention, these salt are included in the present invention.Acid salt is preferably pharmaceutically acceptable, form non-toxic salt with suitable acid, for example with the salt of following acid: mineral acid, example hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid or phosphoric acid, or organic acid, as organic carboxylic acid, for example oxyacetic acid, toxilic acid, hydroxymaleic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, Whitfield's ointment, 0-acetoxy-benzoic acid, or organic sulfonic acid: 2-ethylenehydrinsulfonic acid, first tosic acid or naphthalene-2-sulfonic acid.
Except pharmacy acceptable salt, other salt is also included among the present invention.They can or be used as intermediate at the purifying of compound in the preparation of other compound such as pharmaceutically-acceptable acid addition, perhaps be used for discriminating, CHARACTERISTICS IDENTIFICATION or purifying.
The present invention also comprises solvate, the solvate of ether for example, as Yu the solvate of diox and tetrahydrofuran (THF), or the solvate of alcohol, as with methyl alcohol and alcoholic acid solvate.
The present invention also comprises the method for producing above-mentioned general formula (I) compound, and this method comprises makes following formula: compound Wherein H-Y is
Figure A9511713300131
Or And R 4, R 5, R 6, R 7, R 11, R 12With P with above define identical,
React with following formula: compound:
Figure A9511713300133
Wherein Q is a leavings group, for example halogen, or methanesulfonate or tosylate, and Z, X, R 1, R 2, R 3, n and m be with above definition.
This reaction preferably under 80-110 ℃ of temperature at inert organic solvents, for example carry out in methyl iso-butyl ketone (MIBK) or the acetonitrile, be reflected under the alkaline condition and carry out, for example with yellow soda ash or salt of wormwood.
Formula V compound or known perhaps prepares with methods known in the art.For example wherein H-Y is
Figure A9511713300141
Formula V compound Tetrahydropyridoindoderivatives can be as preparation as described in the following example:
Make the piperidines-3-ketone and the salt of wormwood of suitable hydrazine and N-protected carry out following reaction:
Figure A9511713300142
Then,, slough blocking group with palladium and gac hydrogenation more then with alkali reaction with acetate and hydrochloric acid.
Wherein H-Y is
Figure A9511713300143
The Tetrahydropyridoindoderivatives intermediate can be with the suitable N-protected piperidin-4-one-preparation of similar approach by for example following formula
Figure A9511713300151
The haloethyl benzimidazolone of formula (VI) and thione compounds or known compound perhaps can prepare with standard method, for example make following formula: compound: With formula Q ' (CR 2R 3) nThe Q reaction, wherein Q and Q ' are leavings groups.
Another production approach of The compounds of this invention is the condensation that two basic built-up sections of The compounds of this invention molecule carry out similarly, reverse, and for example makes following formula: compound:
Figure A9511713300161
React with following formula: compound:
Figure A9511713300162
Wherein Q is a leavings group.
These reagent can be by method preparation mentioned above or similar.
Be understandable that, as one or more R 9, R 10And R 6When being not hydrogen, can be connected these groups on the corresponding position by alkylation.
As mentioned above, The compounds of this invention has useful central nervous system activity.This compound is to serotonin, 5-HT ID αAcceptor has activity.At Zgombick, J.M. wait the people, Molecular Pharmacology, Vol.40,1992, The compounds of this invention has showed it in conjunction with activity in the described test of P1036-1042, and hereinafter the Ki value of the described The compounds of this invention of embodiment is some compound of 20nM to 5000nM, and for example the formula III compound also has 5-HT ID βThe combination of acceptor is active.In addition, at Leysen, people such as J.E., Molecular Pharmacology, Vol.21,1981, in the described test of P301-314, The compounds of this invention has shown the activity to the 5-HT2A acceptor.
Because The compounds of this invention is to the selectivity avidity of 5-HT acceptor, they can be used for treating multiple disease, for example obesity, exessive appetite, alcoholism, pain, depression, hypertension, aging, the loss of memory, sexual disorder, anxiety, schizophrenia, functions of intestines and stomach disorder, headache, cardiovascular disorder, smoking cessation syndromes, dopy and vomiting.
The compounds of this invention all is effectively in very wide dosage range, and actual dosage depends on multiple factor such as used specific compound, the symptom of treatment, the mammiferous type or the size of being treated.But the required dosage scope is generally every day 0.01 to 20mg/kg, and when for example treating the grownup, using dosage is 0.5-100mg every day.
The compounds of this invention is usually with oral or drug administration by injection, and for this reason, compound uses with the form of pharmaceutical composition usually.These pharmaceutical compositions prepare with the pharmaceutical field known technology, and comprise at least a active compound.
Therefore, the present invention also comprises pharmaceutical composition, and it contains active ingredient formula (I) compound or its pharmacy acceptable salt or solvate, also is combined with pharmaceutically acceptable vehicle.In the preparation of the present composition, normally active ingredient is mixed with carrier, or with carrier dilution, or the carrier of in the formulation of capsule, sachet, paper or other container, it being packed into.Vehicle can be solid, semisolid or fluent material, the carrier of their effect such as active ingredient, vehicle or medium.The example of some appropriate excipients is: lactose, glucose, sucrose, Sorbitol Powder, N.F,USP MANNITOL, various starch, full silk tree glue, calcium phosphate, algin acid esters, tragacanth gum, gelatin, syrup, methylcellulose gum, methyl hydroxybenzoate and propyl ester, talcum, Magnesium Stearate or oil.If desired, can make the present composition to the formulation that can make the active ingredient snap-out release after patient's medication, continue release or postpone to discharge.
According to the route of administration difference, can make tablet for oral use, capsule or suspension agent to foregoing, as the injection solution or the suspension of parenteral use, or make suppository.Preferably composition is made unit dosage form, contain 0.5-100mg in each dosage, more usually contain 1 to 100mg active ingredient.
The following examples have illustrated the present invention:
Embodiment 11-[2-(1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl)-1-ethyl]-1,3-dihydro-benzimidazolyl-2 radicals-ketone
1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles (1.509,8.7mmol) be suspended in methyl iso-butyl ketone (MIBK) (50ml), in mixture, add 1-(2-(chloroethyl)-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone (1.9589,9.58mmol), add simultaneously yellow soda ash (1.1109,10.45mmol) and tetrabutylammonium iodide (10mg), at rare gas element (N 2) in the atmosphere, add hot suspension to 90 ℃, heated 2 days.The mixture vacuum concentration to doing, is added water (70ml), then add 2N HCl to pH1.Mixture CHCl 3(2 * 70ml) extractions are alkalized to pH10 with 5NNaOH, use CHCl again 3(3 * 70ml) extractions.Organic phase is merged, use the salt water washing, separate, use MgSO 4Dry.The solid that obtains chromatography (CHCl 3, MeOH (2%)) and purifying generation yellow solid, m.p.214-216 ℃.
Embodiment 22-((3, the 3-dimethyl) oxindole base) ethanol
3,3-dimethyl oxindole (1.1 equivalent) is dissolved in anhydrous dimethyl formamide, adds sodium hydride (60% mineral oil suspension) (1.1 equivalent) in batches, and mixture was stirred 1 hour in 25 ℃ in nitrogen.Add 2-(2-chloroethoxy) tetrahydrochysene-2H-pyrans (1 equivalent), add the sodium iodide of catalytic amount simultaneously, in 70 ℃ of stirrings 12 hours, solvent was removed in decompression to reaction mixture then in nitrogen.The oil that obtains is distributed organic phase drying (MgSO between ethyl acetate and water 4), filter and decompression under be evaporated to dried.The oil that obtains is dissolved in methyl alcohol, stirs together, remove solvent after 8 hours and replace ethyl acetate in room temperature and tosic acid.This solution washs secondary with saturated sodium bicarbonate solution, dry (MgSO 4), filter and be evaporated to dried, the oil that obtains provides 2-((3, the 3-dimethyl) oxindole) ethanol with silica gel column chromatography purifying (with 1: 1 wash-out of ethyl acetate/hexane).1-(2-(1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl)-1-ethyl)-1,3-dihydro-3,3-dimethyl-2H-indol-2-one
2-((3, the 3-dimethyl) oxindole) ethanol and triethylamine (1.1 equivalent) are dissolved in methylene dichloride, are cooled to 0 ℃, in nitrogen atmosphere, stir and adding methylsulfonyl chloride (1 equivalent).After stirring the mixture 30 minutes, with it with the washing of cold dilute hydrochloric acid, dry (MgSO 4), filter and be concentrated into dried.The oil that obtains is dissolved in acetonitrile and adds tetrahydrochysene-β-Ka Lin (1 equivalent) solution that contains salt of wormwood (2.5 equivalent) and potassiumiodide (0.1 equivalent), and reaction mixture refluxed in nitrogen atmosphere 3 days.Solvent is removed in decompression, and resistates is dissolved in ethyl acetate.This solution with water washing (X2), dry (MgSO 4), filtration, reduction vaporization be to doing, the oil that chromatogram purification on silica gel (eluent ethylacetate/methyl alcohol) is obtained is dissolved in ethyl acetate, adding toxilic acid (1 equivalent), freezing this solution 12 hours, the collection white crystals obtains 1-, and (2-(1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl)-the 1-ethyl)-1,3-dihydro-3,3-dimethyl-2H-indol-2-one, be monoethyl maleate, m.p.156-158 ℃.1-(2-(2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-2-yl)-1-ethyl)-1,3-dihydro-3,3-dimethyl-2H-indol-2-one
This compound is by tetrahydrochysene-r-carboline and 2-((3, the 3-dimethyl)-oxindole) ethanol method for preparing, with the monoethyl maleate isolated in form, and m.p.111-114 ℃.1-(2-(1-methyl)-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl)-1-ethyl)-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone
This compound is prepared with standard method by 1-chloroethyl benzimidazolone and racemic tetrahydroharman (JCSPerkI (1983) 265), with the monoethyl maleate isolated in form, and m.p.174-176 ℃.1-(2-(3-methyl)-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl)-1-ethyl)-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone
This compound is by 1-chloroethyl benzimidazolone and 3-methyl isophthalic acid, and 2,3,4-β-Ka Lin (Chem.Abs.597501g) separates m.p.183-186 ℃ with the standard method preparation with its hydrochloride form.
Embodiment 36-chloro-1-(2-(1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl) ethyl)-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone
With yellow soda ash (0.403g, 3.8mmol) the churned mechanically 6-chloro-1-of adding (2-mesyloxy ethyl)-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone (1g, 3.443mmol) (USP4,035,369) in the suspension of isobutyl methyl ketone (30ml), reflux and mechanical stirring are 24 hours in nitrogen, cooling, vacuum evaporating solvent, resistates distribute between water (100ml) and ethyl acetate (100ml), and water extracts (2 * 100ml) again with ethyl acetate, merge, wash with water and dry (MgSO 4).Remove by filter sal epsom, vacuum-evaporation filtrate obtains the orange resistates, it is ground with ether obtain yellow solid, with this solid flash chromatography on silica gel purifying (MeOH/CHCl 3, 5: 95) and obtain benzimidazolone, m.p.138-140 ℃.
Embodiment 43-(mesyloxy ethyl) benzothiazole quinoline-2-ketone
(methylene dichloride 21mmol) (10ml) drips of solution is added to 3-(2-hydroxyethyl) benzothiazole quinoline-2-ketone (3.9g, 20mmol) (J.J.D ' Amico and F.G.Bollinger for 1.625ml, 2.4g methylsulfonyl chloride while stirring; J.Heterocyclic Chemistry1988,25,1601) and triethylamine (3.478ml, 2.525g is in methylene dichloride 25mmol) (80ml) solution, and stirring at room 1 hour.Reaction mixture washes with water then, dry (MgSO 4), filtering, vacuum evaporating solvent obtains title product.3-(2-(1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl)-ethyl)-1,3-dihydro-benzothiazole quinoline-2-ketone
With salt of wormwood (1.105g, 8.00mmol) add 1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles (1.144g, 6.65mmol) and 3-(2-mesyloxy ethyl) benzothiazole quinoline-2-ketone (1.815g, 6.648mmol) acetonitrile (50ml) solution, reflux and mechanical stirring are 24 hours in nitrogen.The excessive acetonitrile of vacuum-evaporation provides white solid, and it is distributed between ethyl acetate and water (150ml, 1: 1), separates then.Water layer is used ethyl acetate (75ml) extraction again, and the combined ethyl acetate fraction washes with water and dry (MgSO 4), vacuum boils off solvent, obtains yellow solid, uses purified by flash chromatography on magnetic glue, washes out with ethyl acetate, obtains title compound, m.p.109-111 ℃.
Embodiment 53-(2-mesyloxy ethyl) benzoxazole quinoline-2-ketone
With methylsulfonyl chloride (2.21ml, 3.265g, 28.5mmol) add 3-(the 2-hydroxyethyl) benzoxazole quinoline-2-ketone (5g stirring, 27.933mmol) (J.HeterocyclicChemistry 1988,25,1601) and triethylamine (5.947ml, 4.318g, 42.75mmol) methylene dichloride (60ml) solution, at room temperature stirred 3 days.Vacuum evaporating solvent, resistates distributes between water and ethyl acetate, with hydrochloric acid (2M, 5 * 50ml), sodium bicarbonate (2 * 20ml) washings, dry (MgSO 4), filtering also, vacuum removal solvent obtains title compound.3-(2-(1,2,3, the 4-tetrahydropyridine is [3,4-b] indoles-2-yl also) ethyl) benzoxazole quinoline-2-ketone
With the salt of wormwood (0.828g in the acetonitrile (30ml), 6mmol), ((1.494g is 5.814mmol) with 1,2 for 2-mesyloxy ethyl) benzoxazole quinoline-2-ketone for 3-, 3, the 4-tetrahydropyridine is [3,4-b] indoles (1g, 5.814mmol) 16 hours vacuum evaporating solvents of reflux in nitrogen also, resistates distributes between ethyl acetate (80ml) and water (30ml), separate water outlet, add hydrochloric acid 0.5M, 40ml).Filter and collect the white depositions that obtains, it is suspended in sodium hydroxide, and (2M, 60ml), (3 * 50ml) wash with chloroform.The combined chloroform extraction liquid is used outer (30ml) washing, dry (MgSO with it 4), solution is filtered and vacuum-evaporation.(3: 1,40ml) processing obtained thin flocculent deposit to resistates with ether/ethyl acetate.The filtrate vacuum-evaporation that obtains, resistates obtains title product, m.p.135-137 ℃ with silica gel chromatography purifying (ethyl acetate/40-60 sherwood oil 3: 2).
Embodiment 62-tertbutyloxycarbonyl-1,2,3,4-tetrahydropyridine be [3,4-b] indoles also
With the di-t-butyl carbonic ether (6.35g 29.09mmol) adds 1,2,3, the 4-tetrahydropyridine also [3,4-b] indoles (5g, 29.07mmol) in the two-phase mixture of 2M sodium hydroxide (100ml) and methylene dichloride (80ml), stirring is 20 hours under the room temperature.Isolate dichloromethane layer,, it is washed dry (MgSO with 1M hydrochloric acid (100ml) and sodium hydrogen carbonate solution with methylene dichloride (120ml) aqueous phase extracted, water phase separated, combined dichloromethane layer 4).Filter and collect sal epsom, filtrate flow provides protection and β-Ka Lin through vacuum-evaporation.2-tertbutyloxycarbonyl-9-methyl isophthalic acid, 2,3, the 4-tetrahydropyridine is [3,4-b] indoles also
In nitrogen while stirring 2-tertbutyloxycarbonyl-1,2,3,4-tetrahydroxy pyrido [3,4-b] indoles (2g, THF 7.353mmol) (25ml) drips of solution adds the oil suspension (50%0.388g of sodium hydride, 0.194g, 8.088mmol) in, add DMF (5ml) after 1 hour, stir add after 30 minutes methyl iodide (0.546ml, 1.245g, 8.088mmol), add methyl iodide (2ml after 2 hours again, 4.56g 29.626mmol), mixture was in stirring at room 16 hours.Mixture distributes between water (150ml) and ethyl acetate (150ml) in the back, and (2 * 50ml) extract water again with ethyl acetate.The combined ethyl acetate extraction liquid is with dilute hydrochloric acid (1M, 2 * 50ml) and water washing, dry (MgSO 4), to filter and collect sal epsom, vacuum-evaporation filtrate provides methylated β-Ka Lin.The 9-methyl isophthalic acid, 2,3, the 4-tetrahydropyridine is [3,4-b] indoles also
With trifluoroacetic acid (3.5ml, 45.23mmol) adding 2-tertbutyloxycarbonyl-9-methyl isophthalic acid, 2,3,4-tetrahydropyridine also [3,4-b] indoles (1.848g, 6.461mmol) methylene dichloride (25ml) solution, stirred under the room temperature 3 hours, with methylene dichloride (125ml) dilution, with 2M sodium hydroxide (2 * 50ml) and water washing, dry (MgSO 4).Filter and collect sal epsom, vacuum-evaporation filtrate obtains title compound.9-methyl isophthalic acid-(2-(1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl) ethyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone
At churned mechanically 9-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles (1.08g, 5.81mmol), 1-(2-chloroethyl)-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone (1.14g, 5.81mmol), yellow soda ash (0.6625g, 6.25mmol) and the mixture of isobutyl methyl ketone (30ml) in add sulfonation tetra-n-butyl ammonium (100mg), 90 ℃ of heating 24 hours, cooling made it to leave standstill 48 hours.Vacuum evaporating solvent, resistates distributes between water and ethyl acetate, with ethyl acetate layer drying (MgSO 4), filter vacuum evaporating solvent.The resistates that obtains is impure, with preparation HPLC purifying (60% acetonitrile, 40% water 0.1%NH 3) obtain title product.M.p.166-167 ℃ (toluene).
Embodiment 71-phenyl methyl-3-[2-(1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl)-1-ethyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone list hydrochloride
1-[2-(1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl)-the 1-ethyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone (1.0g, 3.0mmol) be dissolved in DMF (10ml), add 60% sodium hydride (0.132g, 3.3mmol), mixture stirred 10 minutes in nitrogen at ambient temperature.(0.39ml 3.31mmol), stirred this solution 24 hours at ambient temperature to add bromotoluene.
With the mixture vacuum concentration, add water (50ml), precipitation is extracted to chloroform (in 3 * 50ml), with dried over mgso, filtration and vacuum concentration.The solid that obtains is dissolved in ethyl acetate (20ml), uses the hydrogen chloride gas bubbling.The precipitation that obtains obtains cream-colored precipitation, m.p.215-217 ℃ with the methanol recrystallization.
Make following compound with similar approach: 1-methyl-3-[2-(1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl)-1-ethyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, m.p.182-184 ℃ (with the hydrochloride isolated in form).
Embodiment 87-fluoro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles
(0.511g, 2.38mmol) water-soluble (9ml) add Glyoxylic acid hydrate-hydrate (0.241g 6-fluorine tryptamines hydrochloride, 2.618mmol), then add KOH (0.129g, 2.31mmol), stir the solid obtain at ambient temperature 1 hour, and once added concentrated hydrochloric acid (0.6ml) afterwards.Mixture was refluxed 30 minutes, add concentrated hydrochloric acid (0.6ml) again, mixture 15 minutes again refluxes.With the mixture cooling, alkalize to pH12 with 5N sodium hydroxide, (4 * 75ml), dried over mgso is used in separation, and filtering also, vacuum concentration obtains pale solid with chloroform extraction.
Prepare following compound (also can be, publication number 0620222) with similar approach referring to European Patent Application No. 94302608.8:
The 7-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles;
7-methyl-8-bromo-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles;
6-methyl-8-chloro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles;
6-fluoro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles.1-[2-(6-methoxyl group-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl) ethyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone
6-methoxyl group-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles (1.5g, 7.42mmol) be suspended in methyl iso-butyl ketone (MIBK) (35ml), to wherein adding 1-chloroethyl-1, and 3-dihydro-2H-benzimidazolyl-2 radicals-ketone (1.605g, 8.16mmol), yellow soda ash (0.944g, 8.904mmol) and tetrabutylammonium iodide (0.030g), in nitrogen in 90 ℃ of heated mixt 2 days.The mixture vacuum concentration, water-soluble (75ml), the usefulness chloroform extraction (3 * 50ml), use MgSO 4Drying is filtered, vacuum concentration, and the oil that obtains obtains yellow solid with silica gel, chloroform and methyl alcohol through purified by flash chromatography, m.p.116-117 ℃.
Make following compound with similar approach:
1-[2-(6-fluoro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl)-1-ethyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, m.p.115-117 ℃;
1-[2-(8-chloro-6-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl)-1-ethyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, m.p.188-189 ℃;
1-[2-(8-bromo-7-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl)-1-ethyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, m.p.141-143 ℃;
1-[2-(7-fluoro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl)-1-ethyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, m.p.104-106 ℃.
Embodiment 96-skatoxyl
Lithium aluminum hydride (3.48g, 91.70mmol) being suspended in sodium exsiccant tetrahydrofuran (THF) (150ml), stirred suspension in nitrogen atmosphere is indoles-6-base methyl-formiate (8.0g, 45.7mmol) be dissolved in anhydrous tetrahydro furan (50ml), and it is added drop-wise in the lithium aluminum hydride suspension liquid.Stirred this mixture at ambient temperature 3 hours, and dripped water (10ml), then drip 2N hydrochloric acid (30ml) again, (3 * 150ml) generate lilac oil to mixture with ethyl acetate extraction.The 6-skatole
(6.135g 41.69mmol) is dissolved in ethanol (70ml), and 10% palladium/carbon (0.610g) is suspended in acetate (70ml), and it is added in the above-mentioned ethanolic soln the 6-oxyindole.High-pressure hydrogenation device with this mixture adding 60psi by Celite diatomite filtration mixture, concentrated the solution that obtains after 20 hours, with the chloroform give solvent, obtained a water white oil with the purified by flash chromatography mixture.6-skatole-3-formaldehyde
At-5 ℃, with 10 fens clock times phosphoryl chloride (3.2ml, 34.3mmol) be added drop-wise in the dimethyl formamide (26ml), in this solution, add 6-skatole (3.307g with 10 fens clock times again, 25.2mmol) dimethyl formamide (32ml) solution, make mixture slowly be warming up to envrionment temperature, then in 50 ℃ of heating 4 hours.Mixture is cooled to room temperature, in the impouring ice (500g), the aqueous solution was left standstill 16 hours again.Behind the sodium hydroxide (6.0g) water-soluble (22ml) it being added drop-wise in the above-mentioned brown solution, make the yellow mercury oxide boiling and the heat filtering that obtain, placement makes it to be cooled to room temperature, be cooled to 5 ℃ again, leach the washing of precipitation and water (800ml), promote also with pump and further obtained yellow solid in 16 hours 50 ℃ of vacuum-dryings.6-methyl-3-(2-nitro ethylidene)-1H-indoles
6-skatole-2-formaldehyde (3.5g, 21.99mmol) be suspended in Nitromethane 99Min. (60ml), add ammonium acetate (0.562g, 7.3mmol), mixture refluxed in nitrogen 3 hours, mixture and add again ammonium acetate (0.762g, 9.9mmol), mixture refluxed 9 hours again, left standstill 13 hours in room temperature then.Further cool off with ice bath, vacuum filtration, suction dried, and then, obtain orange solids 50 ℃ of vacuum-dryings.The 6-methyltryptamine
Lithium aluminum hydride (3.993g, 105mmol) be suspended in sodium exsiccant tetrahydrofuran (THF) (95ml), suspension usefulness-ice bath cooling, with 15 fens clock times to wherein dripping 6-methyl-3-(2-nitro ethylidine)-indoles (3.723g, tetrahydrofuran (THF) 18.41mmol) (80ml) solution.This mixture was refluxed in nitrogen 16 hours, be chilled to room temperature, further cool off again with ice bath.Drip water (120ml) in mixture, add ether (200ml) again, decant goes out organic solution, and (2 * 200ml) extract water with ether.Combined ether fraction and usefulness 2N salt acid elution (2 * 200ml), isolate water layer, alkalize to pH12 with 50% sodium hydroxide.With its with extracted with diethyl ether (2 * 200ml), separate, obtain cream-colored solid with dried over sodium sulfate, filtration and vacuum concentration.1-[2-(7-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl)-1-ethyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone
The 7-methyl isophthalic acid, 2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles (0.400g, 21.4mmol) be dissolved in N-Methyl pyrrolidone (5ml), in this mixture, add 1-chloroethyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone (0.454g, 2.31mmol), salt of wormwood (0.739g, 5.35mmol) and sodium iodide (0.385g, 2.57mmol), with said components in nitrogen in 80 ℃ the heating 3 hours.Mixture is cooled in room temperature and the impouring water (20), leach the throw out that obtains and wash with water (3 * 20ml), in 50 ℃ of vacuum-dryings, obtain yellow solid through purified by flash chromatography, m.p.119-121 ℃ with silica gel/chloroform/methanol.
Obtain following compound with similar approach:
1-[2-(8-chloro-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl)-1-ethyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, m.p.110-112 ℃;
1-[2-(7-methoxyl group-1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-yl)-1-ethyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, m.p.105-107 ℃.
Embodiment 107-fluoro-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
4-piperidone hydrochloride-hydrate (4.55g) and 3-fluorobenzene hydrazine hydrochloride (4.85g) are added ethanol (80ml), and mixture heating up refluxed 1 hour.With hydrogen chloride gas bubbling in mixture, and then refluxed 1.5 hours.Solution is cooled to 0 ℃, hydrochloride is leached, use washing with alcohol, be dissolved in boiling water, with activated carbon decolorizing and filtration.In hot solution, add the 2M sodium hydroxide solution until reaching neutral,, leach evaporated milk oil colours solid, wash with water and drying with the test paper test.The white solid that obtains with the acetonitrile recrystallization is 7-fluorine and 9-fluorine mixture of isomers, and its ratio is 86: 14 (HPLC).
With this method (J.Chem.Soc. (C), 1968,1235-1243) prepare following known compound:
8-fluoro-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles, m.p.210 ℃ (usp3,419,568) (by the preparation of 4-fluorobenzene hydrazine hydrochloride);
2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles, m.p.226 ℃ of (J.Chem.Soc. (C), 1968,1235-1243, and J.Med.Chem.1966,436-438 (by the preparation of phenylhydrazine hydrochloride); And
6-fluoro-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles, m.p.220 ℃ (by the preparation of 2-fluorobenzene hydrazine hydrochloride).1-[2-(2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-2-yl)-1-ethyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone
2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (2.15g) are dissolved in anhydrous acetonitrile (150ml), to the sodium iodide that wherein adds catalytic amount, and salt of wormwood (2.25g) and 1-chloroethyl-1,3-dihydro-2 H-benzimidazolyl-2 radicals-ketone (2.8g).Reflux also stirred the mixture 48 hours, and filtering heat solution is removed inorganics, vacuum-evaporation, resistates grinds with acidic alcohol, leaches hydrochloride and uses washing with alcohol, and it is dissolved in the boiling water, filter,, solid is leached, washes with water and drying with the alkalization of 50% sodium hydroxide.Rough solid is dissolved in the chloroform that contains 5% methyl alcohol, makes it (flash) to fill in by a silica gel " fast ", evaporation is ground with acetonitrile, leaches solid, uses washing with alcohol.Make that recrystallization obtains Dan diox thing, m.p.114-117 ℃ in the solid Zai diox.
Make following compound: 1-[2-(8-fluoro-2,3,4,5-tetrahydrochysene-1H-pyrido [4 with similar approach, 3-b] indoles-2-yl)-the 1-ethyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, mp200.5-201.5 ℃ (by 8-fluoro-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles)
1-[2-(6-fluoro-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-2-yl)-1-ethyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone hydrochloride, m.p.214-216 ℃ (by 6-fluoro-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles); With
1-[2-(7-fluoro-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-2-yl)-the 1-ethyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, m.p.125-127 ℃, the 9-isomer that contains 6-10% is (by 7-fluoro-2,3,4, the 5-tetrahydrochysene-1H)-pyrido [4,3-b] indoles (+14%9-isomer) preparation).
Embodiment 11
Every tablet of tablet that contains the 10mg activeconstituents is pressed the method preparation:
Activeconstituents 10mg
Starch 160mg
Microcrystalline Cellulose 100mg
Polypyrrole alkane ketone (being 10% aqueous solution) 13mg
Sodium starch glycolate 14mg
Magnesium Stearate 3mg
Total amount 300mg
Activeconstituents, starch and Mierocrystalline cellulose uniform mixing, make polypyrrole alkane ketone solution and the above-mentioned powder mixes that obtains, sieve.The dry particle that so obtains after sieve, adds sodium starch glycolate and Magnesium Stearate then in particulate matter, mix the back is pressed into every heavy 300mg with tablet agent tablet.
Embodiment 12
Every content of dispersion is that the capsule of 20mg is pressed the method preparation:
Activeconstituents 20mg
Dry starch 178mg
Magnesium Stearate 2mg
Total amount 200mg
Activeconstituents, starch and Magnesium Stearate are sieved, pack in the hard gelatine capsule with every Intake Quantity 200mg.

Claims (8)

1. following formula: compound and its salt and solvate:
Figure A9511713300021
R wherein 1And R 7Each is halogen, trifluoromethyl, C naturally 1-6Alkyl, C 1-6Alkoxyl group, the heteroaryl of selecting phenyl, the naphthyl of selecting replacement that replaces or selecting to replace; R 2And R 3Each is hydrogen or C naturally 1-6Alkyl; R 4And R 5Hydrogen, halogen, trifluoromethyl, C naturally 1-6Alkyl, C 1-6Alkoxyl group, the heteroaryl of selecting phenyl, the naphthyl of selecting replacement that replaces or selecting to replace; R 6Be hydrogen, C 1-6The heteroaryl that alkyl, the phenyl of selecting replacement, the naphthyl of selecting replacement, selection replace, phenyl-C that selection replaces 1-6Alkyl or-CO 2R 8, R wherein 8It is ester group; M and p each naturally 0,1,2,3 or 4, n is 1,2,3 or 4, Z is ,-O-,-S-or
Figure A9511713300032
R wherein 9And R 10Each is hydrogen, C naturally 1-6Phenyl-C that alkyl or selection replace 1-6Alkyl; X is oxygen or sulphur; And Y is
Figure A9511713300033
Or
Figure A9511713300034
R wherein 11And R 12Each is hydrogen, C naturally 1-6The heteroaryl that the phenyl that alkyl, trifluoromethyl, selection replace is selected the naphthyl that replaces or selected to replace.
2. according to the compound of claim 1, its compound is a following formula: compound:
Figure A9511713300035
3. according to the compound of claim 2, wherein X is an oxygen.
4. according to the compound of claim 3, wherein Z is And R 9Be hydrogen or C 1-6Alkyl.
5. according to the compound of claim 1, wherein Z is , X is an oxygen, R wherein 9Be hydrogen or C 1-6Alkyl, and m is 0,1 or 2, n is 1 or 2, R 4, R 5And R 6Be hydrogen.
6. following formula: compound and its salt:
Figure A9511713300043
R wherein 9Be hydrogen or C 1-6Alkyl, R 1 ', R 1 ", R 7 'And R 7 "Hydrogen, halogen, C respectively do for oneself 1-6Alkyl or C 1-6Alkoxyl group, R5 are hydrogen or trifluoromethyl, and Y is
Figure A9511713300051
Or
7. pharmaceutical preparation contains compound or its pharmacy acceptable salt or the solvate of claim 1, contains pharmaceutically acceptable diluent or carrier simultaneously.
8. claim 1 compound or its pharmacy acceptable salt or solvate are as the application of medicine.
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Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2308362A (en) * 1995-12-19 1997-06-25 Lilly Industries Ltd Pharmaceutical indole derivatives
EP0905136A1 (en) 1997-09-08 1999-03-31 Janssen Pharmaceutica N.V. Tetrahydro gamma-carbolines
UA70334C2 (en) * 1998-10-06 2004-10-15 Janssen Pharmaceutica N V Jans BENZOTHIENO[3,2-c]PYRIDINES AS a2 ANTAGONISTS BENZOTHIENO[3,2-c]PYRIDINES AS a2 ANTAGONISTS
UA74826C2 (en) * 2000-05-17 2006-02-15 Ortho Mcneil Pharm Inc ?-carboline derivatives as phosphodiesterase inhibitors
US20040067991A1 (en) * 2000-07-06 2004-04-08 Greig Nigel H Tetrahydrobenzothiazole analogues as neuroprotective agents
DE10040016A1 (en) * 2000-08-16 2002-02-28 Boehringer Ingelheim Pharma Novel beta-amyloid inhibitors, process for their preparation and their use as pharmaceuticals
US6586435B2 (en) 2000-09-19 2003-07-01 Boehringer Ingelheim Pharma Kg Benzimidazolone derivatives displaying affinity at the serotonin and dopamine receptors
AU2001293804A1 (en) * 2000-09-19 2002-04-02 Boehringer Ingelheim Pharma Kg New benzimidazolone derivatives displaying affinity at the serotonin and dopamine receptors
WO2002024661A2 (en) * 2000-09-19 2002-03-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg New n, n'-disubstituted benzimidazolone derivatives with affinity at the serotonin and dopamine receptors
US7183410B2 (en) 2001-08-02 2007-02-27 Bidachem S.P.A. Stable polymorph of flibanserin
US6849640B2 (en) 2001-08-08 2005-02-01 Pharmacia & Upjohn Company Therapeutic 1H-pyrido [4,3-b] indoles
US10675280B2 (en) 2001-10-20 2020-06-09 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
UA78974C2 (en) 2001-10-20 2007-05-10 Boehringer Ingelheim Pharma Use of flibanserin for treating disorders of sexual desire
EP1912650B8 (en) 2005-08-03 2017-10-18 Sprout Pharmaceuticals, Inc. Use of flibanserin in the treatment of obesity
CA2626134C (en) 2005-10-29 2013-12-24 Boehringer Ingelheim International Gmbh Benzimidazolone derivatives for the treatment of premenstrual and other female sexual disorders
CA2654798C (en) 2006-06-30 2015-01-13 Boehringer Ingelheim International Gmbh Flibanserin for the treatment of urinary incontinence and related diseases
WO2008019996A2 (en) 2006-08-14 2008-02-21 Boehringer Ingelheim International Gmbh Formulations of flibanserin and method for manufacturing the same
CL2007002214A1 (en) 2006-08-14 2008-03-07 Boehringer Ingelheim Int PHARMACEUTICAL COMPOSITION IN THE FORM OF COMPRESSED, WHERE AT LEAST THE LENGTH OF THE COMPRESSED IN THE PREVIOUS STATE OF THE APPLICATION IS AT LEAST 7/12 OF THE PILOR DIAMETER OF THE PATIENT AND AFTER INGERING IT IN THE FOOD STATE, THE LENGTH OF THE COMP
BRPI0716436B8 (en) 2006-08-25 2021-05-25 Boehringer Ingelheim Int controlled release system and method for manufacturing it
UY31335A1 (en) 2007-09-12 2009-04-30 VASOMOTOR SYMPTOMS TREATMENT
EP3355884B1 (en) 2015-10-01 2021-04-28 Olema Pharmaceuticals, Inc. TETRAHYDRO-1H-PYRIDO[3,4-b]INDOLE ANTI-ESTROGENIC DRUGS

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4035369A (en) 1975-10-08 1977-07-12 Janssen Pharmaceutica N.V. 1-Benzazolylalkyl-4-substituted-piperidines
IL69132A (en) * 1982-07-14 1986-02-28 Roussel Uclaf Benzo-and naphtho-thiopyranopyrimidinones,their preparation and pharmaceutical compositions containing them
FR2661177A1 (en) * 1990-04-23 1991-10-25 Rhone Poulenc Sante DERIVATIVES OF NAPHTOSULTAM ANTAGONISTS OF SEROTONIN, THEIR PREPARATION AND THE MEDICINES CONTAINING THEM

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102428080A (en) * 2009-05-29 2012-04-25 住友化学株式会社 Agent for treatment or prevention of diseases associated with activity of neurotrophic factors

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